Human immunodeficiency virus-associated nephropathy (HIVAN) is a distinct clinico-pathological entity that is characterized by focal segmental glomerular sclerosis (FSGS) and tubulointerstitial lesions. Preliminary studies by others and us have indicated that many of the effects of HIV-1 infection are mediated via oxidative stress which results from the generation of reactive oxygen species (ROS). Recently, pivotal role of p66ShcA proteins have been identified in the generation of oxidative stress. The long term objective of the present proposal is to develop novel therapeutic strategies, targeting mutant genes or dysfunctional gene products, to arrest or prevent the development of HIVAN. Our recent preliminary studies in Tg26 (a mouse model of HIVAN) animals have shown that both glomerular and tubular cells showed enhanced generation of ROS. In addition, in in vitro studies, podocytes-transduced with HIV-1 not only showed enhanced expression of p66ShcA but also demonstrated increased generation of ROS; whereas, p66ShcA-deficient podocytes showed attenuated generation of ROS. Based on these results we hypothesize that in HIV-1 infection, inhibition of p66ShcA activates a Foxo3A- dependent stress program that promotes the survival phenotype. We further hypothesize that deletion of p66ShcA from the genome of Tg26 mice will not only attenuate or prevent HIV-1-induced oxidative stress, but also delay or prevent the progression of renal lesions. In the present proposal we will 7 Test the hypothesis that inhibition of p66ShcA in HIV-1-infected podocytes activates a Foxo3-dependent stress program that promotes the survival phenotype 7 Test the hypothesis that deletion of p66ShcA from the genome of Tg26 mice will delay or prevent the progression of renal lesions 7 Test the hypothesis that HIV-1-induced p66ShcA redox function and dysregulation of the mTOR pathway leads to renal pathogenesis associated with HIVAN The outcome of these studies will help us in the development of therapeutic strategies to treat this devastating renal disease.